tbuckley/cabot-search huggingface dataset:
Phospholamban pentamerization increases sensitivity and dynamic range of cardiac relaxation
Authors: Florian Funk, Annette Kronenbitter, Katarzyna Hackert, Matthias Oebbeke, Gerhard Klebe, Mareike Barth, Daniel Koch, Joachim P Schmitt
Journal: Cardiovascular Research (2023)

A key event in the regulation of cardiac contraction and relaxation is the phosphorylation of phospholamban (PLN) that relieves the inhibition of the sarco/endoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a). PLN exists in an equilibrium between monomers and pentamers. While only monomers can inhibit SERCA2a by direct interaction, the functional role of pentamers is still unclear. This study investigates the functional consequences of PLN pentamerization.We generated transgenic mouse models expressing either a PLN mutant that cannot form pentamers (TgAFA-PLN) or wild-type PLN (TgPLN) in a PLN-deficient background. TgAFA-PLN hearts demonstrated three-fold stronger phosphorylation of monomeric PLN, accelerated Ca2+ cycling of cardiomyocytes, and enhanced contraction and relaxation of sarcomeres and whole hearts in vivo. All of these effects were observed under baseline conditions and abrogated upon inhibition of protein kinase A (PKA). Mechanistically, far western kinase assays revealed that PLN pentamers are phosphorylated by PKA directly and independent of any subunit exchange for free monomers. In vitro phosphorylation of synthetic PLN demonstrated that pentamers even provide a preferred PKA substrate and compete with monomers for the kinase, thereby reducing monomer phosphorylation and maximizing SERCA2a inhibition. However, β-adrenergic stimulation induced strong PLN monomer phosphorylation in TgPLN hearts and sharp acceleration of cardiomyocyte Ca2+ cycling and haemodynamic values that now were indistinguishable from TgAFA-PLN and PLN-KO hearts. The pathophysiological relevance of PLN pentamerization was evaluated using transverse aortic constriction (TAC) to induce left ventricular pressure overload. Compared to TgPLN, TgAFA-PLN mice demonstrated reduced survival after TAC, impaired cardiac haemodynamics, failure to respond to adrenergic stimulation, higher heart weight, and increased myocardial fibrosis.The findings show that PLN pentamerization greatly impacts on SERCA2a activity as it mediates the full range of PLN effects from maximum inhibition to full release of SERCA2a function. This regulation is important for myocardial adaptation to sustained pressure overload.
Limited Song Mixing Without Genomic Gene Flow in a Contact Zone Between Two Songbird Species
Authors: Lei Wu, Jing Dang, Linfang Tang, Yalin Cheng, Gang Song, Yuehua Sun, Jochen Martens, Martin Päckert, Per Alström, Dezhi Zhang, Chenxi Jia, Fumin Lei
Journal: Molecular Biology and Evolution (2023)

Abstract Song is considered to play an important role in the maintenance of prezygotic reproductive isolation between closely related songbird species. Therefore, song mixing in a contact zone between closely related species is often considered as evidence of hybridization. The Sichuan Leaf Warbler Phylloscopus forresti and the Gansu Leaf Warbler Phylloscopus kansuensis, which diverged 2 million years ago, have formed a contact zone in the south of the Gansu Province of China, where mixed songs have been observed. In this study, we investigated the potential causes and consequences of song mixing by integrating bioacoustic, morphological, mitochondrial, and genomic data with field ecological observations. We found that the two species display no apparent morphological differences, whereas their songs differ dramatically. We demonstrated that ∼11% of the males in the contact zone sang mixed songs. Two males singing mixed song were genotyped, and both were found to be P. kansuensis. Despite the presence of mixed singers, population genomic analyses detected no signs of recent gene flow between the two species, although two possible cases of mitochondrial introgression were identified. We conclude that the rather limited song mixing does not lead to, or result from, hybridization, and hence does not result in the breakdown of reproductive barriers between these cryptic species.
Polishing De Novo Nanopore Assemblies of Bacteria and Eukaryotes With FMLRC2
Authors: Q X Charles Mak, Ryan R Wick, James Matthew Holt, Jeremy R Wang
Journal: Molecular Biology and Evolution (2023)

Abstract As the accuracy and throughput of nanopore sequencing improve, it is increasingly common to perform long-read first de novo genome assemblies followed by polishing with accurate short reads. We briefly introduce FMLRC2, the successor to the original FM-index Long Read Corrector (FMLRC), and illustrate its performance as a fast and accurate de novo assembly polisher for both bacterial and eukaryotic genomes.
Letter to the editor: Association between birth weight, preterm birth, and nonalcoholic fatty liver disease in a community-based cohort
Authors: Fahim Ebrahimi, Jonas F. Ludvigsson
Journal: Hepatology (2023)

To the editor, While we commend Amadou et al.1 for their fine study reporting a U-shaped association between birth weight and risk of NAFLD, we have some concerns. NAFLD was defined using the fatty liver index. This index was, however, developed as a risk stratification tool (not as a diagnostic instrument) and has a rather low positive predictive value for the diagnosis of NAFLD (67%).2 Furthermore, the fatty liver index may perform poorly in young individuals with normal body mass index,3 as in the current French study population (mean age 38 y, normal body mass index).1 Given that the fatty liver index formula is largely driven by body mass index and waist circumference, the question arises whether the found associations rather explain a higher risk of obesity and would especially miss individuals with lean NAFLD. While in women, there was a positive association between high birth weight and risk of NAFLD, the mediation analysis revealed that in men high birth weight did neither have a direct nor a total effect on the later risk of NAFLD—in contrast the indirect effect seemed even protective. Against this background, how do the authors explain the contradictive results on high birth weight and NAFLD risk in men andwomen? The authors found a slight negative association between birth weight and the Forns index, which was used as proxy for liver fibrosis. Here, we see two limitations that make the interpretation of these results challenging: first, the Forns index was originally developed to noninvasively rule-out significant fibrosis and has not been validated to be used as a continuous variable. Second, it was derived in high-risk cohorts of patients with chronic hepatitis C infection,4 while the current study applied it in a general population setting. Hence, we are eager to know if the authors could confirm these results using FIB-4 instead, which is recommended by international guidelines.5
Hydrogel-forming microarray patch mediated transdermal delivery of tetracycline hydrochloride
Authors: Li Zhao, Lalitkumar K. Vora, Stephen A. Kelly, Linlin Li, Eneko Larrañeta, Helen O. McCarthy, Ryan F. Donnelly
Journal: Journal of Controlled Release (2023)

Antibiotic resistance is one of the most serious health problems today and is expected to worsen in the coming decades. It has been suggested that antibiotic administration routes that bypass the human gut could potentially tackle this problem. In this work, an antibiotic hydrogel-forming microarray patch (HF-MAP) system, which can be used as an alternative antibiotic delivery technology, has been fabricated. Specifically, poly(vinyl alcohol)/poly(vinylpyrrolidone) (PVA/PVP) microarray showed excellent swelling properties with >600% swelling in PBS over 24 h. The tips on the HF-MAP were proven to be able to penetrate a skin model which is thicker than stratum corneum. The antibiotic (tetracycline hydrochloride) drug reservoir was mechanically robust and dissolved completely in an aqueous medium within a few minutes. In vivo animal studies using a Sprague Dawley rat model showed antibiotic administration using HF-MAP achieved a sustained release profile, in comparison with animals receiving oral gavage and intravenous (IV) injection, with a transdermal bioavailability of 19.1% and an oral bioavailability of 33.5%. The maximum drug plasma concentration for HF-MAP group reached 7.40 ± 4.74 μg/mL at 24 h, whereas the drug plasma concentration for both oral (5.86 ± 1.48 μg/mL) and IV (8.86 ± 4.19 μg/mL) groups peaked soon after drug administration and had decreased to below the limit of detection at 24 h. The results demonstrated that antibiotics can be delivered by HF-MAP in a sustained manner.
Myeloproliferative neoplasms and splanchnic vein thrombosis: Contemporary diagnostic and therapeutic strategies
Authors: Jean‐Jacques Kiladjian, Bruno Cassinat
Journal: American Journal of Hematology (2023)

Myeloproliferative neoplasms (MPNs) are the most common etiologies of primary splanchnic vein thrombosis, present in almost forty percent of patients with Budd-Chiari syndrome or portal vein thrombosis. Diagnosis of MPNs can be difficult in these patients because key characteristics, such as elevated blood cell counts and splenomegaly, are confounded by portal hypertension or bleeding complications. In recent years, diagnostic tools have improved to provide more accurate diagnosis and classification of MPNs. Although bone marrow biopsy findings remain a major diagnostic criterion, molecular markers are playing an increasing role not only in diagnosis but also in better estimating prognosis. Therefore, though screening for JAK2V617F mutation should be the starting point of the diagnostic workup performed in all patients with splanchnic vein thrombosis, a multidisciplinary approach is needed to accurately diagnose the subtype of myeloproliferative neoplasm, recommend the useful additional tests (bone marrow biopsy, search for an additional mutation using targeted next-generation sequencing), and suggest the best treatment strategy. Indeed, providing a specific expert care pathway for patients with splanchnic vein thrombosis and underlying myeloproliferative neoplasm is crucial to determine the optimal management to reduce the risk of both hematological and hepatic complications.
Vascular endothelial growth factor-D plasma levels and <i>VEGFD</i> genetic variants are independently associated with outcomes in patients with cardiovascular disease
Authors: Pia Davidsson, Susanna Eketjäll, Niclas Eriksson, Anna Walentinsson, Richard C Becker, Anders Cavallin, Anna Bogstedt, Anna Collén, Claes Held, Stefan James, Agneta Siegbahn, Ralph Stewart, Robert F Storey, Harvey White, Lars Wallentin
Journal: Cardiovascular Research (2023)

The vascular endothelial growth factor (VEGF) family is involved in pathophysiological mechanisms underlying cardiovascular (CV) diseases. The aim of this study was to investigate the associations between circulating VEGF ligands and/or soluble receptors and CV outcome in patients with acute coronary syndrome (ACS) and chronic coronary syndrome (CCS).Levels of VEGF biomarkers, including bFGF, Flt-1, KDR (VEGFR2), PlGF, Tie-2, VEGF-A, VEGF-C, and VEGF-D, were measured in the PLATO ACS cohort (n = 2091, discovery cohort). Subsequently, VEGF-D was also measured in the STABILITY CCS cohort (n = 4015, confirmation cohort) to verify associations with CV outcomes. Associations between plasma VEGF-D and outcomes were analysed by multiple Cox regression models with hazard ratios (HR [95% CI]) comparing the upper vs. the lower quartile of VEGF-D. Genome-wide association study (GWAS) of VEGF-D in PLATO identified SNPs that were used as genetic instruments in Mendelian randomization (MR) meta-analyses vs. clinical endpoints. GWAS and MR were performed in patients with ACS from PLATO (n = 10 013) and FRISC-II (n = 2952), and with CCS from the STABILITY trial (n = 10 786). VEGF-D, KDR, Flt-1, and PlGF showed significant association with CV outcomes. VEGF-D was most strongly associated with CV death (P = 3.73e-05, HR 1.892 [1.419, 2.522]). Genome-wide significant associations with VEGF-D levels were identified at the VEGFD locus on chromosome Xp22. MR analyses of the combined top ranked SNPs (GWAS P-values; rs192812042, P = 5.82e-20; rs234500, P = 1.97e-14) demonstrated a significant effect on CV mortality [P = 0.0257, HR 1.81 (1.07, 3.04) per increase of one unit in log VEGF-D].This is the first large-scale cohort study to demonstrate that both VEGF-D plasma levels and VEGFD genetic variants are independently associated with CV outcomes in patients with ACS and CCS. Measurements of VEGF-D levels and/or VEGFD genetic variants may provide incremental prognostic information in patients with ACS and CCS.
Insulin/IGF Axis and the Receptor for Advanced Glycation End Products: Role in Meta-inflammation and Potential in Cancer Therapy
Authors: Veronica Vella, Rosamaria Lappano, Eduardo Bonavita, Marcello Maggiolini, Robert Bryan Clarke, Antonino Belfiore, Ernestina Marianna De Francesco
Journal: Endocrine Reviews (2023)

Abstract In metabolic conditions such as obesity and diabetes, which are associated with deregulated signaling of the insulin/insulin-like growth factor system (IIGFs), inflammation plays a dominant role. In cancer, IIGFs is implicated in disease progression, particularly during obesity and diabetes; however, further mediators may act in concert with IIGFs to trigger meta-inflammation. The receptor for advanced glycation end-products (RAGE) and its ligands bridge together metabolism and inflammation in obesity, diabetes, and cancer. Herein, we summarize the main mechanisms of meta-inflammation in malignancies associated with obesity and diabetes; we provide our readers with the most recent understanding and conceptual advances on the role of RAGE at the crossroad between impaired metabolism and inflammation, toward disease aggressiveness. We inform on the potential hubs of cross-communications driven by aberrant RAGE axis and dysfunctional IIGFs in the tumor microenvironment. Furthermore, we offer a rationalized view on the opportunity to terminate meta-inflammation via targeting RAGE pathway, and on the possibility to shut its molecular connections with IIGFs, toward a better control of diabetes- and obesity-associated cancers.
Association of accelerometer-derived circadian abnormalities and genetic risk with incidence of atrial fibrillation
Authors: Lulu Yang, Hongliang Feng, Sizhi Ai, Yue Liu, Binbin Lei, Jie Chen, Xiao Tan, Christian Benedict, Ningjian Wang, Yun Kwok Wing, Lu Qi, Jihui Zhang
Journal: npj Digital Medicine (2023)

Evidence suggests potential links between circadian rhythm and atrial fibrillation (AF). However, whether circadian disruption can predict the onset of AF in the general population remains largely unknown. We aim to investigate the association of accelerometer-measured circadian rest-activity rhythm (CRAR, the most prominent circadian rhythm in humans) with the risk of AF, and examine joint associations and potential interactions of CRAR and genetic susceptibility with AF incidence. We include 62,927 white British participants of UK Biobank without AF at baseline. CRAR characteristics, including amplitude (strength), acrophase (timing of peak activity), pseudo-F (robustness), and mesor (height), are derived by applying an extended cosine model. Genetic risk is assessed with polygenic risk scores. The outcome is the incidence of AF. During a median follow-up of 6.16 years, 1920 participants developed AF. Low amplitude [hazard ratio (HR): 1.41, 95% confidence interval (CI): 1.25-1.58], delayed acrophase (HR: 1.24, 95% CI: 1.10-1.39), and low mesor (HR: 1.36, 95% CI: 1.21-1.52), but not low pseudo-F, are significantly associated with a higher risk of AF. No significant interactions between CRAR characteristics and genetic risk are observed. Joint association analyses reveal that participants with unfavourable CRAR characteristics and high genetic risk yield the highest risk of incident AF. These associations are robust after controlling for multiple testing and in a series of sensitivity analyses. Accelerometer-measured CRAR abnormalities, characterized by decreased strength and height, and later timing of peak activity of circadian rhythm, are associated with a higher risk of AF in the general population.
Cost-effectiveness of Sodium-Glucose Cotransporter-2 Inhibitors for Patients With Heart Failure and Preserved Ejection Fraction—Living on the Edge
Authors: Alexander T. Sandhu, David J. Cohen
Journal: JAMA Cardiology (2023)

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Improved survival of patients with primary plasma cell leukemia with <scp>VRd</scp> or daratumumab‐based quadruplets: A multicenter study by the Greek myeloma study group
Authors: Eirini Katodritou, Efstathios Kastritis, Dimitra Dalampira, Sosana Delimpasi, Emmanouil Spanoudakis, Vasiliki Labropoulou, Ioannis Ntanasis‐Stathopoulos, Annita‐Ioanna Gkioka, Nikos Giannakoulas, Nikolaos Kanellias, Theodosia Papadopoulou, Aggeliki Sevastoudi, Eyrydiki Michalis, Maria Papathanasiou, Maria Kotsopoulou, Anastasia Sioni, Theodora Triantafyllou, Aikaterini Daiou, Mavra Papadatou, Marie‐Christine Kyrtsonis, Anastasia Pouli, Ioannis Kostopoulos, Evgenia Verrou, Meletios‐Athanasios Dimopoulos, Evangelos Terpos
Journal: American Journal of Hematology (2023)

Abstract We evaluated the efficacy and prognostic impact of bortezomib‐lenalidomide triplet (VRd) or daratumumab‐based quadruplets (DBQ) versus previous anti‐myeloma therapies, that is, bortezomib standard combinations (BSC) or conventional chemotherapy (CT), in a large cohort of patients with primary plasma cell leukemia (pPCL), including those fulfilling the revised diagnostic criteria, that is, circulating plasma cells (cPCS): ≥5%; 110 pPCL patients (M/F: 51/59; median age 65 years, range: 44–86) out of 3324 myeloma patients (3%), registered in our database between 2001 and 2021, were studied; 37% had cPCS 5%–19%; 89% received novel combinations including DBQ (21%), VRd (16%) and BSC (52%); 35% underwent autologous stem cell transplantation. 83% achieved objective responses. Treatment with VRd/DBQ strongly correlated with a higher complete response rate (41% vs. 17%; p = .008). After a median follow‐up of 51 months (95% CI: 45–56), 67 patients died. Early mortality was 3.5%. Progression‐free survival was 16 months (95% CI: 12–19.8), significantly longer in patients treated with VRd/DBQ versus BSC/CT (25 months, 95% CI: 13.5–36.5 vs. 13 months 95% CI: 9–16.8; p = .03). Median overall survival (OS) was 29 months (95% CI: 19.6–38.3), significantly longer in patients treated with VRd/DBQ versus BSC/CT (not reached vs. 20 months, 95% CI: 14–26; 3‐year OS: 70% vs. 32%, respectively; p &lt; .001; HzR: 3.88). In the multivariate analysis VRd/DBQ therapy, del17p(+) and PLT &lt;100.000/μL, independently predicted OS ( p &lt; .05). Our study has demonstrated that in the real‐world setting, treatment with VRd/DBQ induces deep and durable responses and is a strong prognostic factor for OS representing currently the best therapeutic option for pPCL.
Insulin-like growth factor binding protein 4 loaded electrospun membrane ameliorating tendon injury by promoting retention of IGF-1
Authors: Hui Wang, Ruyue Yu, Meng Wang, Shikun Wang, Xingyu Ouyang, Zhiwen Yan, Shuai Chen, Wei Wang, Fei Wu, Cunyi Fan
Journal: Journal of Controlled Release (2023)

Tendon injury is one of the most common musculoskeletal disorders that impair joint mobility and lower quality of life. The limited regenerative capacity of tendon remains a clinical challenge. Local delivery of bioactive protein is a viable therapeutic approach for tendon healing. Insulin-like growth factor binding protein 4 (IGFBP-4) is a secreted protein capable of binding and stabilizing insulin-like growth factor 1 (IGF-1). Here, we applied an aqueous-aqueous freezing-induced phase separation technology to obtain the IGFBP4-encapsulated dextran particles. Then, we added the particles into poly (L-lactic acid) (PLLA) solution to fabricate IGFBP4-PLLA electrospun membrane for efficient IGFBP-4 delivery. The scaffold showed excellent cytocompatibility and a sustained release of IGFBP-4 for nearly 30 days. In cellular experiments, IGFBP-4 promoted tendon-related and proliferative markers expression. In a rat Achilles tendon injury model, immunohistochemistry and quantitative real-time polymerase chain reaction confirmed better outcomes by using the IGFBP4-PLLA electrospun membrane at the molecular level. Furthermore, the scaffold effectively promoted tendon healing in functional performance, ultrastructure and biomechanical properties. We found addition of IGFBP-4 promoted IGF-1 retention in tendon postoperatively and then facilitated protein synthesis via IGF-1/AKT signaling pathway. Overall, our IGFBP4-PLLA electrospun membrane provides a promising therapeutic strategy for tendon injury.